Intra-arterial delivery of FePt nanoparticles induces ferroptosis and immune infiltration to enhance radiotherapy.

Recent advances in nanomedicine provide new opportunities to enhance radiotherapy and overcome tumor radioresistance. In this study, we investigated the therapeutic potential of iron-platinum nanoparticles (FePt NPs) delivered through intra-arterial (IA) administration to improve tumor targeting and therapeutic efficacy. FePt NPs significantly inhibited the proliferation of triple-negative breast cancer (TNBC) cells and enhanced radiosensitivity. Mechanistic studies demonstrated that FePt NPs induced ferroptosis characterized by lipid peroxidation (LPO), mitochondrial damage, and downregulation of GPX4, leading to the release of damage-associated molecular patterns (DAMPs), including ATP, high-mobility group box 1 (HMGB1), and calreticulin (CRT), thereby promoting ferroptosis-associated immunogenic cell death (ICD). In vitro cytokine array analysis further revealed modulation of immune-related cytokines associated with inflammatory responses and immune cell recruitment. In vivo studies showed that IA administration significantly increased FePt NPs accumulation within tumors compared with conventional intravenous delivery, resulting in enhanced tumor suppression. The combination of FePt NPs and radiotherapy further promoted T-cell and macrophage infiltration within the tumor microenvironment (TME), indicating enhanced immune activation. Importantly, in a comparative canine liver tumor model treated with FePt NPs via transarterial embolization, tumor regression or stabilization was observed together with increased immune infiltration. These findings demonstrate that IA-delivered FePt NPs act as ferroptosis-inducing radiosensitizers that reshape the tumor immune microenvironment and convert immunologically "cold" tumors into "hot" tumors. This approach highlights the translational potential of localized nanoparticle delivery for cancer radio-immunotherapy.